Endometrial (uterine) cancer is the most common gynecological malignancy in Europe and North America. It is the seventh most common cause of death from cancer in women in Western-Europe, accounting for 1%-2% of all deaths from cancer. According to the most recent NCCN guidelines, pathologist review differentiates uterine cancer in three distinct types: i) pure endometrioid carcinoma, ii) serous or clear cell adenocarcinoma, and iii) carcinosarcoma, i.e. a mixed type of carcinoma and sarcoma (NCCN Guidelines®, Version 2.2015). The distinction between endometrioid and serous carcinomas of the endometrium is important for prognostic and therapeutic purposes. Endometrioid carcinomas typically are confined to the uterus and have better prognosis than endometrial serous carcinomas that have frequent peritoneal dissemination and a worse prognosis (K. Garg and R. A. Soslow in Arch. Pathol. Lab. Med., Vol. 138, March 2014, 335-342).
Uterine serous carcinoma (USC), or uterine papillary serous carcinoma, accounts for approx. 10% of endometrial cancer. This subtype of endometrial cancer is biologically highly aggressive and causes the most endometrial cancer deaths. Molecular profiling studies have demonstrated HER2 to be one of the most over-expressed genes in USC. HER2 is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. HER2 over-expression has been reported to range from 18% to 80% in USC due to several factors like tumour type and stage of the tissue sample as well as the immunohistochemistry (IHC) technique used (A. D. Santin et al. in Clin. Cancer Res., 8, 2002, 1271-1279; B. M. Slomovitz et al. in J. Clin. Oncol. 22, 2004, 3126-3132). Up to 35% of USCs may over-express the HER2 oncogene at high level by immunohistochemistry (i.e. HER2 IHC 3+) or harbour HER2 gene amplification by fluorescence in situ hybridization (i.e. FISH positive). An additional 45% of USCs express HER2 at moderate (i.e. HER2 IHC 2+) or low (i.e. HER2 IHC 1+) levels.
Trastuzumab (Herceptin™, Genentech/Roche) is a recombinant humanized IgG1 monoclonal antibody against the extracellular domain of HER2 and is currently approved for the treatment of both metastatic and early-stage breast cancer as well as locally advanced or metastatic gastric cancer over-expressing HER2. Case study reports describe the use of trastuzumab in endometrial cancer. In the Int. J. Gynecol. Cancer 16: 1370-1373, 2006, E. Jewell et al. describe a positive result of the administration of trastuzumab to one patient with metastatic endometrial cancer. In the Int. J. Gynecol. Obstet. 102: 128-131, 2008, A. D. Santin et al. report the results of treatment with trastuzumab in two patients with advanced or recurrent endometrial carcinoma that over-express HER2. In Gynecol. Oncol. 116: 15-20, 2010, Fleming et al. report results of a Phase II trial of 34 patients who had HER2-positive endometrial carcinoma and were treated with trastuzumab. Trastuzumab has not currently been approved for the treatment of any endometrial cancer.
D. P. English et al. report in Cancer Medicine published by John Wiley & Sons Ltd., pp. 1-10, 2014, that T-DM1 is highly effective against primary HER2 over-expressing uterine serous carcinoma (USC) in vitro and in vivo. T-DM1 (Kadcyla™, ado-trastuzumab emtansine, Genentech/Roche) is an antibody-drug conjugate which comprises trastuzumab covalently linked to the anti-microtubule agent DM1. DM1 belongs to the maytansine class of chemotherapeutic agents. On average, 3-4 molecules of DM1 are conjugated to each trastuzumab molecule. T-DM1 is an agent aimed at delivering the highly potent DM1 into HER2 over-expressing cells via receptor-mediated endocytosis. T-DM1 has been approved for the treatment of patients with HER2-positive metastatic breast cancer who received prior treatment with trastuzumab and a taxane. The authors conclude that T-DM1 shows promising antitumor effect in HER2-positive USC cell lines and USC (i.e. HER2 IHC 3+) xenografts in SCID mice (15 mg/kg, i.p. injections once per week) and its activity is significantly higher when compared to trastuzumab, and that T-DM1 may represent a novel treatment option for HER2-positive USC patients with disease refractory to standard chemotherapy. No clinical investigations are currently ongoing with T-DM1 for the treatment of endometrial cancer.